A control strategy using variable speed limit (VSL) is a proven solution to reduce freeway collision risks and improve safety. However, the heterogeneity of human drivers restricts the effectiveness of traditional VSL controls, which may be made up by recent advanced technologies of connected and automated vehicles (CAVs). This study aims to propose a CAV-based VSL control system to address the limitations caused by human drivers on VSL control’s effectiveness. First, the heterogeneity of human drivers is analyzed, and its impact on the safety performance of VSL is examined. Specifically, a microscopic simulation platform is established, and two vehicle dynamic models developed for CAVs and human-driven vehicles (HDVs) are incorporated into the simulation platform. Based on a widely utilized surrogate safety measurement, time-to-collision, its derivative metrics are applied to evaluate collision risks, and the total travel time is used to assess operational efficiency. Extensive simulations are conducted to examine the performance of the proposed CAV-VSL system. The results indicate the following: (1) the heterogeneity of human drivers negatively affects the performance of the VSL; (2) the performance of the proposed control system in a mixed flow can be improved by advanced wireless communication technology; (3) CAVs are able to implement the VSL control strategy effectively resulting in the proactive reduction of the heterogeneity.